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Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Novartis, Horsham, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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1 mRNA expression was significantly elevated 7
days after conidia challenge and remained elevated until day 21. In
contrast, IL-13R2 mRNA expression, although constitutively expressed
in naive lung, was absent in the lungs of A.
fumigatus-sensitized mice both before and after conidia
challenge. Membrane-bound IL-4R mRNA expression was significantly
elevated 7 days after conidia challenge; however, soluble IL-4R mRNA
expression was increased 30 days after conidia challenge.
Immunoneutralization of IL-13 between days 14 and 30 or days 30 and 38
after fungal sensitization and challenge significantly attenuated
airway hyperresponsiveness, collagen deposition, and goblet cell
hyperplasia at day 38 after conidia challenge; however, the effects of
IL-4 immunoneutralization during the same time periods were not as
marked. IFN-
and IL-12 release after Aspergillus Ag
restimulation was elevated from spleen cells isolated from mice treated
with IL-4 anti-serum compared with IL-13 anti-serum or normal
rabbit serum-treated mice. This study demonstrates a pronounced
therapeutic effect of IL-13-immunoneutralization at extended time
points following the induction of chronic asthma. Most importantly,
these therapeutic effects were not reversed following cessation of
treatment, and IL-13 anti-serum treatment did not alter the
systemic immune response to Ag restimulation, unlike IL-4
immunoneutralization. Therefore, IL-13 provides an attractive
therapeutic target in allergic asthma. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To date, the majority of experimental studies investigating the role of IL-13 or IL-4 in allergic airway inflammatory response have used either gene-targeted knockout mice, immunoneutralization, or receptor antagonists. These studies have demonstrated a major role for these cytokines during sensitization or acute allergen challenge periods of up to 72 h (4, 5, 6). At present, little is known about the potential therapeutic use for targeting these cytokines in a model of chronic allergic airway disease that persists for several weeks. We have recently developed a chronic model of Aspergillus fumigatus-induced allergic asthma that exhibits the characteristic pulmonary phenotype of asthmatics, including local and systemic allergic inflammation associated with a chronic pulmonary eosinophilia, elevated IgE levels, chronic airway remodeling, and reversible airway obstruction (7, 8, 9). Allergic responses to A. fumigatus spores or conidia can promote major complications in atopic (allergic) individuals and asthmatics (10, 11). Chronic airway remodeling in these individuals often leads to a poor clinical outcome. Thus, in this study we investigated the potential therapeutic effect of IL-13-, and in comparison, IL-4-immunoneutralization in this chronic model of fungal asthma.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Sensitization of mice CBA/J mice to a commercially available preparation of soluble A. fumigatus Ags (Greer Laboratories, Lenoir, NC) was performed as previously described in detail (12).
Immunoneutralization of IL-13 or IL-4
Immunoneutralization of IL-13 or IL-4 was conducted by i.p.
injection of 0.5 ml of anti-murine IL-13 or IL-4 antiserum (titer
of 106/ml; Ref. 13) at 2-day
intervals according to three dosing protocols (see Fig. 1
). The volume
of antiserum was considered to be sufficient to neutralize systemic
endogenous IL-13 or IL-4 in that the biological half-life of the Ab was
48 h (13). Anti-murine IL-13 or IL-4 polyclonal Abs
were raised by immunizing New Zealand White rabbits with recombinant
murine IL-13 or IL-4 (R&D Systems, Minneapolis, MN). Polyclonal Abs
were titered by direct ELISA, and these Abs recognized murine IL-13 or
IL-4 at a dilution of 1 x 10-6. The Abs
did not cross-react with other assayed murine recombinant cytokines and
chemokines. As a control, preimmune normal rabbit serum (NRS) was used.
The endotoxin content in both anti-IL-13 and IL-4 antiserum and NRS
was below detection level (<0.05 enodtoxin U/ml Pyrogent;
BioWhittaker, Walkersville, MD).
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Thirty-eight days after intratracheal A. fumigatus conidia challenge, bronchial hyperresponsiveness to methacholine (10 µg i.v.) in A. fumigatus–sensitized mice was assessed in a Buxco (Troy, NY) plethysmograph (14). At the conclusion of the assessment of airway responsiveness, blood was collected for serum isolation, bronchoalveolar lavage was performed, and whole lungs were finally dissected from each mouse and snap-frozen in liquid N2 or prepared for histological analysis.
ELISA analysis
Murine IL-4, IL-13, IL-12, IFN-, and TGF-
protein levels
were determined in 50 µl of whole lung homogenates, using a
standardized sandwich ELISA technique previously described in detail
(15).
Whole lung histological analysis
Whole lungs from A. fumigatus-sensitized mice before and after A. fumigatus conidia challenge were fully inflated by intratracheal perfusion with 4% paraformaldehyde. Lungs were then dissected and placed in fresh paraformaldehyde for 24 h. Routine histological techniques were used to paraffin-embed this tissue, and 5-µm sections of whole lung were stained with Masson trichrome (for determination of collagen deposition) or periodic acid-Schiff (PAS; for identification of goblet cell hyperplasia and mucus production).
Measurement of collagen
Collagen content in whole lung homogenates from A. fumigatus-sensitized mice treated with NRS, polyclonal anti-IL-13, or anti-IL-4 Abs was measured according to instructions using a collagen assay purchased from Biocolor (Westbury, NY).
Preparation of cDNA and RT-PCR amplification
Total RNA samples were prepared from whole lungs removed
from mice at 0, 3, 7, 21, and 30 days after conidia challenge using the
one-step Trizol isolation procedure (Life Technologies). RNA from
specific samples were reverse transcribed into cDNA using a BRL reverse
transcription kit and oligo(dT)12-18 primer. The amplification solution
contained 50 mM KCl, 10 mM Tris-HCl (pH 8.3), and 2.5 mM
MgCl2. Specific oligonucleotide primers were
added (200 ng/sample) to the buffer, along with a 5-µl reverse
transcribed cDNA sample. The following oligonucleotide primers were
used. IL-4R primer sequences: sense 5'–3'; antisense, 5'–3' bp
product. IL-13R1 primer sequences: sense
5'-GAATTTGAGCGTCTCTGTCGAA-3'; antisense,
5'-GGTTATGCCAAATGCACTTGAG-3' 308-bp product. IL-13R2 primer
sequences: sense 5'-ATGGCTTTTGTGCATATCAGATGCT-3'; antisense,
5'-CAGGTGTGCTCCATTTCATTCTAAT-3' 800-bp product. For soluble and
membrane IL-4R primer sequences: sense 5'-AGTGAGTGGAGTCCTAGCATC-3';
antisense, 5'-GCTGAAGTAACAGAACAGGC-3'. sIL-4R, 241 bp and mIL-4R, 127
bp (16). -actin primer sequences: sense
5'-GCTCGGCCGTGGTGGTGAAGC-3'; antisense, 5'-GTGGGGCGCCCCAGGCACCA-3'
450-bp product.
The cDNA was amplified using the following cycling parameters. The mixture was first incubated for 4 min at 94°C and cycled 38 times at 94°C for 45 s (denatured), annealing at 55°C or 66°C (IL-4R or IL-13R, respectively) for 60 s, and elongated at 72°C for 45 s. After amplification, the samples were separated on a 2% agarose gel containing 0.3 µg/ml ethidium bromide, and bands were visualized and photographed using a translucent UV source.
Ag restimulation of isolated spleen cells
Whole spleens were isolated from mice following protocol 2 at
day 38. RBC were lysed following mechanical separation, and spleen
cells were plated onto six-well plates at 1 x
107 cells/well. Supernatants were collected, and
IFN- or IL-12 levels were measured by ELISA after incubation of the
spleen cells with medium or A. fumigatus-soluble Ag (50
µg) for 24 h.
Statistical analysis
All results are expressed as mean ± SEM. ANOVA and Dunnett’s test for multiple comparisons were used to determine statistical significance in both groups at various times after conidia challenge; p < 0.05 was considered statistically significant.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Transgenic overexpression of IL-13 or IL-4 in the murine lung has
been shown to generate a complex phenotype that recapitulates many of
the features of clinical asthma (3, 17). These
observations have led to several investigations into the role of IL-13
and IL-4 in acute allergic airway disease in mice. In this study we
have examined the role of IL-13 and IL-4 in a murine model of A.
fumigatus-induced chronic fungal asthma (7, 8, 9) that
persists for several weeks following fungal sensitization and conidia
challenge. IL-4 and IL-13 levels in whole lung were increased following
intratracheal conidia challenge in A. fumigatus-sensitized
mice (Fig. 1
). A significant
(p < 0.05) increase in the levels of both IL-4
and IL-13 were measured at day 30 after conidia challenge compared with
the levels in lungs before conidia; however, levels of IL-13 were over
10-fold greater than IL-4. To identify the temporal role of IL-13 and
IL-4 in this model, cytokine immunoneutralization was conducted at
delayed time points after the establishment of allergic airway
inflammation and airway remodeling. IL-13 or IL-4 was neutralized
according to each protocol shown in Fig. 1. IL-4 or IL-13 anti-sera
or NRS was administered every 2 days between days 0 and 14 (protocol
1), days 14 and 30 (protocol 2), or days 30 and 38 (protocol 3) after
the conidia challenge. Airway function, inflammation, and remodeling
were assessed at 38 days after A. fumigatus live conidia
challenge following cessation of immunoneutralization therapy to
determine the therapeutic benefit after attenuation of IL-13 or
IL-4.
Time course of IL-13 and IL-4 receptor expression
IL-4 and IL-13 signal through multimeric receptor complexes. The
IL-4R subunit plays a role in both IL-13 and IL-4 signaling, whereas
the role of the IL-13R subunits is less clear. Two IL-13R
subunits have been identified, IL-13R1 and IL-13R2 chains
(18). IL-13 R1 binds weakly to IL-13, but a heterodimer
consisting of IL-4R and IL-13R1 acts as a functional receptor for
both IL-4 and IL-13. In the present model IL-13R1 mRNA was
constitutively expressed in whole lung before conidia challenge, but
was increased after conidia challenge (Fig. 2). Seven days after conidia challenge a
significant (p < 0.001) increase in IL-13R1
mRNA expression was measured (Fig. 2), which remained elevated at day
21. By 30 days after conidia challenge IL-13R1 mRNA levels had
returned to similar levels measured at day 0 (Fig. 2). In contrast, the
IL-13R2 subunit, although constitutively expressed in naive whole
lung (Fig. 2A, Con), was not detected at any time point
after conidia challenge (Fig. 2A). IL-13R2 alone binds to
its ligand with higher affinity than the IL-13R1 subunit; however,
its functional role, decoy or active, remains unknown
(19). In the context of its function as a decoy receptor,
the absence of IL-13R2 expression in A.
fumigatus-sensitized lung after conidia challenge may leave the
actions of IL-13 unchecked, resulting in exacerbated fibrosis and
goblet cell hyperplasia.
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).
In contrast, sIL-4R mRNA expression was not significantly
(p < 0.001) elevated until 30 days after
conidia challenge (Fig. 3). These results are similar to those found
following infection of mice with Leishmania major
(20), whereby sIL-4R expression was increased. Whereas the
function of the mIL-4R in ligand binding and subsequent signaling
appears obvious, the role of the sIL-4R is less clear. Because the
sIL-4R binds IL-4 with high affinity, it can act as a natural
antagonist of IL-4 activity, competing with the mIL-4R on target cells
for the binding of IL-4.
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AHR is a common feature of human asthma and is defined as an
exaggerated bronchoconstrictor response to various provocative agents.
Both IL-4 and IL-13 have been established as primary effector molecules
in experimental AHR (4, 5); however, IL-13 appears to play
a more important role, as revealed by receptor neutralization and
recombinant cytokine administration. During chronic fungal asthma, AHR
following methacholine challenge increases between 3 and 7 days after
conidia challenge (7, 8, 9) and remains significantly
elevated at 38 days after challenge (basal = 2.1 ± 0.3 to
33.6 ± 4.8 cm H2O/ml/s following
methacholine; Fig. 4). Although
anti-IL-4 reduced airway hyperreactivity by 2-fold in both
protocol 2 and 3, this effect did not reach statistical significance
(Fig. 4, A-C). Similarly, immunoneutralization of IL-13
between days 0 and 14 (protocol 1) did not significantly reduce AHR at
day 38 (Fig. 2A). However, following immunoneutralization of
IL-13 between days 14 and 30 (protocol 2; Fig. 4B) or days
30 and 38 (protocol 3; Fig. 4C), a statistically significant
(p < 0.05) inhibition of AHR to a methacholine
injection was measured compared with controls that correlated
with IL-13R1 mRNA expression during these time points of
immunoneutralization. This inhibitory effect was noted despite the fact
that anti-IL-13 therapy was stopped 8 days before assessment of AHR
in protocol 2. Although our results are consistent with previous
studies, this study is the first, to date, that demonstrates that
attenuation of IL-13, 2 wk after the induction of airway inflammation,
affords a therapeutic effect. Most notably these therapeutic effects
persisted despite the cessation of immunoneutralization therapy.
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subunit (4); however, the role of eosinophils
in IL-13-induced AHR, to date, remains controversial (22, 23). Indeed, Wills-Karp et al. (5) suggested that
IL-13-induced AHR could be disassociated from eosinophilic
inflammation. These findings are consistent with observations in our
chronic fungal asthma model because eosinophil infiltration into the
airways peaks at day 7 following conidia challenge, and eosinophil
numbers largely disappear by day 14, after the conidia are cleared from
the lungs. Thus, in this study the attenuation of eosinophil activity
probably does not account for the therapeutic effects of IL-13
immunoneutralization during chronic fungal asthma. Collagen deposition and subepithelial fibrosis was inhibited using a therapeutic IL-13 neutralization protocol
Collagen deposition and subepithelial fibrosis are characteristic
pathological features of chronic human asthma (24);
however, the role that IL-13 and IL-4 play in the peribronchial
fibrosis associated with chronic asthma has been difficult to
investigate due to the paucity of appropriate in vivo models of
allergic airway disease. Masson trichrome staining (Fig. 5) revealed marked collagen deposition
and subepithelial fibrosis around the airways of A.
fumigatus-sensitized mice at 38 days after conidia challenge.
Compared with the appropriate serum controls, collagen staining was
markedly decreased following the immunoneutralization of IL-13 between
days 14 and 30 (protocol 2) and days 30 and 38 (protocol 3; Fig. 5, B and E). In contrast, immunoneutralization of
IL-4 did not appear to reduce collagen staining (Fig. 5, C
and F). Further confirmation of these histological findings
was observed using a collagen assay. After cessation of IL-13
immunoneutralization, the total soluble collagen content in the lungs
of mice at day 38 was significantly (p < 0.05)
lower than controls when mice were treated according to protocol 2 with
anti-IL-13 (Table I); however,
immunoneutralization of IL-4 did not have a similar effect. No
significant effect on total soluble collagen lung levels was observed
in mice treated according to protocol 3 (anti-IL-13). However, it
was noted that significantly (p < 0.001)
attenuated levels of the profibrotic cytokine, TGF-, were measured
in whole lung homogenates from anti-IL-13-treated mice (protocol 3;
0.337 ± 0.01 to 0.24 ± 0.01 ng/mg protein). Noticeable
differences in pulmonary fibrosis have been previously shown between
IL-13- and IL-4-transgenic mice. IL-4-transgenic mice do not develop
airway fibrosis; however, IL-13-transgenic mice manifest significant
degrees of subepithelial and adventitial fibrosis (3, 25, 26). These results have been clarified in IL-4R knockout and
STAT6-deficient mice, an intracellular signaling pathway that is used
by IL-13 (27, 28) whereby hepatic collagen
deposition was reduced in Schistosome mansoni-infected
animals, whereas collagen responses were normal in IL-4-deficient mice
(29).
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Goblet cell hyperplasia is a characteristic of the remodeled
airway during allergic disease. Mucus hyperproduction from these cells
appears to play a key role in exacerbation of AHR and may contribute
significantly to morbidity and mortality associated with asthma
(30). Furthermore, IL-13-transgenic mice exhibit goblet
cell hypertrophy and mucus hypersecretion (3, 31). The
presence of airway goblet cells was assessed by PAS staining at day 38
after conidia challenge, following treatment with NRS (A),
anti-IL-13 (B), or anti-IL-4 (C) between
days 14 and 30 (protocol 2) or NRS (D), anti-IL-13
(E), or anti-IL-4 (F) between days 30 and 38
(protocol 3; Fig. 6). Goblet cell
hyperplasia in large and small airways was detected in control A.
fumigatus-sensitized mice at 38 days after the conidia challenge
(Fig. 6, A and D). However, immunoneutralization
of IL-13 between days 14 and 30 (protocol 2; Fig. 6B) or
days 30 and 38 (protocol 3; Fig. 6E) completely ablated
goblet cell hyperplasia. Although goblet cells were less prominent
following IL-4 immunoneutralization between days 14 and 30 (Fig. 6C) and days 30 and 38 (Fig. 6F), this effect was
not as marked as that following IL-13 immunoneutralization. These
results are in concordance with results obtained from IL-13-transgenic
studies (3), whereby they demonstrate a critical role for
IL-13 in mucus cell metaplasia; however, the contribution of IL-4 to
goblet cell hyperplasia and mucus production is less well defined.
Similarly to IL-13-transgenic mice, IL-4 overexpressing mice have also
shown increases in PAS-positive material in lavage fluid, suggesting
that IL-4, in addition to IL-13, stimulates mucus production within the
airways (31). However, because IL-4 has been shown to
induce the production of IL-13 from mast cells (32), the
effect of IL-4 on mucus production may be indirect via the release of
IL-13. Therefore, IL-13 immunoneutralization appears to exhibit a more
profound therapeutic effect on the attenuation of goblet cell
hyperplasia than IL-4 that is maintained up to 7 days following
cessation of anti-IL-13 treatment.
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In addition to their effects on allergic airway inflammation and
collagen deposition, IL-4 and IL-13 have important systemic
immunomodulatory effects. Spleen cells isolated from mice treated with
anti-IL-4 Abs responded to restimulation with soluble A.
fumigatus with a robust Th1 response, involving IL-12 and IFN-
secretion (Fig. 7), similar to previous
studies in the absence of IL-4 (29, 33). This demonstrates
that IL-4 neutralization appears to have important systemic
immunomodulatory effects that IL-13 does not possess. In this respect,
IL-13 appears to be a more attractive therapeutic target than IL-4
because it does not alter the systemic immune response.
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1. To overcome
this problem, ongoing studies are addressing the therapeutic utility of
eliminating IL-13 receptor-positive cells during chronic fungal asthma.
The data presented herein suggest that IL-13 may be a more favorable
target than IL-4 in the treatment of the diverse airway manifestations
of chronic asthma. This study also highlights the benefits of IL-13
immunoneutralization over existing asthma therapies because the
beneficial effects of anti-IL-13 treatment persisted even following
cessation of therapy.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kate Blease, Department of Pathology, University of Michigan Medical School 5214 Med Sci I, 1301 Catherine Road, Ann Arbor, MI 48109.
3 Abbreviations used in this paper: AHR, airway hyperresponsiveness; NRS, normal rabbit serum; PAS, periodic acid-Schiff; mIL-4R, membrane-associated IL-4R; sIL-4R, soluble IL-4R.
Received for publication December 20, 2000. Accepted for publication February 9, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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2: molecular cloning, characterization, and comparison with murine IL-13 receptor 1. J. Immunol. 161:2317.-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr. Biol. 8:669.[Medline]This article has been cited by other articles:
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F. Kheradmand, A. Kiss, J. Xu, S.-H. Lee, P. E. Kolattukudy, and D. B. Corry A Protease-Activated Pathway Underlying Th Cell Type 2 Activation and Allergic Lung Disease J. Immunol., November 15, 2002; 169(10): 5904 - 5911. [Abstract] [Full Text] [PDF]
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 J. M. Schuh, K. Blease, S. L. Kunkel, and C. M. Hogaboam Eotaxin/CCL11 is involved in acute, but not chronic, allergic airway responses to Aspergillus fumigatus Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L198 - L204. [Abstract] [Full Text] [PDF]
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K. Blease, J. M. Schuh, C. Jakubzick, N. W. Lukacs, S. L. Kunkel, B. H. Joshi, R. K. Puri, M. H. Kaplan, and C. M. Hogaboam Stat6-Deficient Mice Develop Airway Hyperresponsiveness and Peribronchial Fibrosis during Chronic Fungal Asthma Am. J. Pathol., February 1, 2002; 160(2): 481 - 490. [Abstract] [Full Text] [PDF]
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K. Blease, C. Jakubzick, J. M. Schuh, B. H. Joshi, R. K. Puri, and C. M. Hogaboam IL-13 Fusion Cytotoxin Ameliorates Chronic Fungal-Induced Allergic Airway Disease in Mice J. Immunol., December 1, 2001; 167(11): 6583 - 6592. [Abstract] [Full Text] [PDF]
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